The aim of our laboratory is to understand how genomes are organized in vivo and how this organization contributes to genome function in health and disease. We have made significant progress in several areas: a) We have extended our earlier efforts to develop imaging methods to visualize gene expression in living cells. Recently we have applied these techniques to the analysis of genomes in embryonic stem cells. We have demonstrated that genomes are organized differently in undifferentiated stem cells and that changes in their physical properties are critical for differentiation. These observations have implications for our understanding of embryonic stem cell differentiation and the control of this process. B) We have identified molecular motors as a novel type of tumor-suppressing proteins. While molecular motors have long been implicated in proper chromosome segregation during cell division, we have now documented a critical role for one molecular motor, hKIF4, in preventing aberrant chromosome number. Cells lacking hKIF4 were prone to tumor formation, demonstrating that aberrant chromosome number can trigger tumor formation. These observations represent novel concepts in the field of molecular motor and cancer biology. C) Finally, we are exploring the molecular mechanisms of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). The genetic cause for this fatal childhood disease is a mutation in one of the major architectural proteins of the cell nucleus. We have been able to correct in patient cells the disease-causing alternative splicing event associated with this mutation and were able to rescue the cellular defects observed in patient cells. In addition we have demonstrated that the same molecular mechanism responsible for the diseases is also involved in physiological aging. These observations have identified a novel aging pathway and have established HGPS as a model for the study of human aging. This is of particular interest since, unlike most other premature aging syndromes, HGPS is characterized by the absence of tumors. We are now exploring HGPS as a model system to explore the link between aging and cancer.